Bacteria have a great ability to generate resistance to drugs through lateral gene transfer, mutation of enzymes, or by expressing enzymes which actively pump out the drug or break it down. Over the past 10 years resistance to existing drugs has become a significant problem in many countries. No new antibacterial drugs have been developed over the past 15 years. Vancomycin is currently the drug of last resort to combat the multidrug resistant Gram-positive bacteria In many places vancomycin-resistant Staphylococcus aureus and Enterococci (VRE) have been discovered. There is thus a desperate need for a new antibacterial drug to replace the drug of last resort.
There are a host of cytoplasmic targets for the development of new antibacterials, such as gyrase inhibitors, protein synthesis inhibitors, muramyl cascade inhibitors and many more. The major hurdle in designing such drugs is that in addition to enzyme based activity these drugs need to cross the bacterial cell wall to exert their antibacterial effect. On the other hand, enzymes involved in the stage III synthesis of the bacterial cell wall exist on the cell wall exterior, and therefore drugs inhibiting these enzymes can exert their bactericidal or bacteriostatic effect without having to cross the cell wall. Penicillin, cephalosporin and vancomycin are drugs that act on the transpeptidase enzymes which control the final steps in the peptidoglycan biosynthesis. Moenomycin is known to act on the transglycosylase enzymes, which are similarly involved in the polymerization of disaccharide precursors. Moenomycin displays very high potency at MIC level, and is used in animal feed as a growth promoter.
Moenomycin is a lipid-linked pentasaccharide. Through extensive SAR experiments it was realised that smaller fragments of moenomycin were capable of exerting antibacterial activity. Trisaccharide fragments of moenomycin still display antibacterial activity, but are not sufficiently stable to be useful drugs. On the basis of this, Sofia and coworkers discovered a new series of disaccharides, carrying aromatic substituents in well defined positions around the disaccharide, which displayed significant MIC activity [WO0064915 and WO9926596].
A further class of disaccharide molecules, based on a sub-structure of vancomycin was shown to have antibacterial activity against vancomycin resistant bacteria. This class of molecules was subsequently demonstrated to contain transglycosylase inhibitors, and were not transpeptidase inhibitors as is vancomycin itself [WO9853813].